Immunomodulatory effects of 1,25-dihydroxyvitamin D3 on TH1/TH2 cytokines in inflammatory bowel disease: an in vitro study.

Crohn's disease (CD) is associated with a higher type-1-helper T cell (Th1) cytokine expression, whereas ulcerative colitis (UC) appears to express a modified Th2 response. In addition to its classic role in calcium homeostasis, calcitriol, the hormonal active form of vitamin D, exerts immunoregulatory effects such as modulation of Th1/Th2 cytokines. Therefore, calcitriol administration could modify immune dysfunction in CD and UC. Nine patients with UC (M/F: 5/4; mean age 47 years, remission(R)/active(A) disease: 7/2), 8 patients with CD (M/F: 2/6; mean age 36, R/A 5/3) and 6 healthy controls (HC) (M/F: 3/3, mean age 4) were enrolled. Peripheral blood was collected after a drug-washout of 15 days and peripheral blood mononuclear cells were stimulated with mitogens alone or in the presence of physiological concentrations of calcitriol (100 pg/ml). Type 1 (IL-2, TNF-alpha, IFN-gamma) and type 2 (IL-10) cytokine production was assayed on supernatants by ELISA. Compared to HC, TNF-alpha production was significantly higher both in UC (p=0.0002) and CD (p=0.0001) patients, at baseline and after incubation with calcitriol (UC p=0.0003, CD p=0.0009). The effects of calcitriol incubation were: 1) reduced IFN-gamma (p=0.024) and increased IL-10 (p=0.06) production in UC patients; 2) reduced TNF-alpha production in CD (p=0.032); 3) no significant effects in HC. Calcitriol increased, albeit not significantly, IL-10 production in UC compared to CD patients (p=0.09). These results suggest an important modulatory role of vitamin D in the Th1/Th2 immune response. The observation that the effect of this modulation was different in CD compared to UC patients provides an interesting area of research into the pathogenesis and treatment of these inflammatory conditions.

Omeprazole and sucralfate in the treatment of NSAID-induced gastric and duodenal ulcer.

AIM: To establish the healing efficacy of two drugs, omeprazole and sucralfate, when given to patients who had developed gastric or duodenal ulcer while undergoing chronic treatment with non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: Ninety-eight patients with arthritis or arthrosis and NSAID-related gastric or duodenal ulcer were admitted to the endoscopic, single-blind study. They were randomized to receive either omeprazole 20 mg o.m. or sucralfate 2 g b.d. for 4-8 weeks. The patients continued to receive the same NSAID during the trial. Upper gastrointestinal endoscopy was performed at entry and after 4 or 8 weeks. RESULTS: Eighty-eight patients completed the 4-week study, but only 81 were available for final analysis at 8 weeks. Omeprazole was significantly superior to sucralfate in inducing gastric ulcer healing after both 4 (87 vs. 52%, P = 0.007) and 8 weeks (100 vs. 82%, P = 0.04). No statistically significant difference in duodenal ulcer healing rates emerged between the two groups either at 4 (79 vs. 55%) or 8 weeks (95 vs. 73%). The healing rates in patients with combined gastric and duodenal ulcer were 67 vs. 33% after 4 weeks and 6 7 vs. 6 7% after 8 weeks of treatment. The percentages of asymptomatic patients were similar in the two treatment groups both at 4 (70 vs. 73%) and 8 weeks (70 vs. 75%). H. pylori infection did not influence healing rates, but significantly more H. pylori-positive patients healed with omeprazole. CONCLUSIONS: The results of this study show that omeprazole is superior to sucralfate in healing NSAID-induced gastroduodenal ulcer in patients who continue to take anti-inflammatory drugs. The good results observed were unrelated to H. pylori status.

Peptic ulcer therapy with cimetidine versus tripotassium dicitrato bismuthate in rheumatoid arthritis patients undergoing chronic NSAID treatment.

AIM: To compare the efficacy of cimetidine and tripotassium dicitrato bismuthate (TDB) in arthritic patients who had developed gastric (GU) or duodenal (DU) ulceration while taking non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: Eighty-six rheumatoid arthritis (RA) patients affected by endoscopically proven DU (n = 44) or GU (n = 42), and on chronic NSAID therapy which was not suspended during anti-ulcer therapy, were randomized to cimetidine (400 mg t.d.s.) or TDB (120 mg q.d.s.). A repeat endoscopy was planned after 4 weeks (and 8 weeks, in case of failed healing). The patients who were unhealed after 8 weeks of therapy were allocated to the alternative anti-ulcer drug for a further 8 weeks without interrupting the anti-inflammatory therapy. RESULTS: At week 4 of therapy. 14/24 (58%) DU and 9/20 (45%) GU patients treated with cimetidine were healed, compared with 12/20 (60%) and 10/22 (45%) TDB-treated patients (N.S.). At week 8 of therapy, the DU healing rates were 15/24 (63%) with cimetidine and 14/20 (70%) for TDB. The corresponding GU healing rates were 12/20 (60%) with cimetidine and 13/22 (60%) for TDB (N.S.). At week 16, complete healing with cimetidine was observed in 67% of DU and 57% of GU patients unhealed with TDB; the corresponding figures in the patients crossed to TDB were 83% for DU and 63% for GU patients (N.S. vs. cimetidine). CONCLUSIONS: No statistically significant difference was found between the healing activities of cimetidine and TDB in rheumatoid arthritis patients with peptic ulcer who did not interrupt their NSAID treatment for arthritis. This trial showed that the continued consumption of NSAIDs appears to slow the ulcer healing process, especially in GU patients.

Inflammatory bowel disease approaching the 3rd millennium: pathogenesis and therapeutic implications?

The aetiology of inflammatory bowel disease remains unknown, but genetic, immuno-inflammatory, infectious, vascular and neural factors play an important role. All effective treatments in use today were introduced empirically and most have multiple action. Targeted therapy is very attractive, either with cell and gene therapy or by using specific cytokine inhibitors and inhibitory cytokines. The role of the intestinal milieu, and enteric flora in particular, appears to have a much greater significance than previously appreciated. The reduction of any changes leading to pro-coagulant activity may be a promising line of therapeutic investigation, and measures to reduce platelet aggregation and endothelial cell adhesiveness are examples of therapeutic potentials. Finally, there has been tangible demonstration of the ability of nerves to alter the inflammatory process which will lead to new therapeutic approaches in inflammatory bowel disease.

Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn's disease: a randomised, investigator-blind study.

BACKGROUND AND AIMS: The efficacy of azathioprine in the treatment of chronic active Crohn's disease is well established. However, this drug has a long onset of action. Methotrexate has also been shown to be effective in chronic active Crohn's disease. The aim of this study was to evaluate the efficacy and safety of methotrexate in comparison with azathioprine, and to establish whether methotrexate has a shorter onset of action in this setting. METHODS: Patients with chronic active Crohn's disease were admitted to this investigator-blind study. Chronicity was defined as the need for steroid therapy of > or = 10 mg/day for at least 4 months during the preceding 12 months, with at least one attempt to discontinue treatment. The disease had to be clinically active at entry, with a Crohn's Disease Activity Index of > or = 200. Six patients treated with azathioprine and methotrexate, respectively, were found to have enterocutaneous and perianal fistulas. At entry, all patients received prednisolone (40 mg once a day) which was tapered over a period of 12 weeks unless their clinical condition deteriorated. All patients were randomised to receive i.v. methotrexate 25 mg/week, or oral azathioprine 2 mg/kg per day, for a 6-month follow-up period. After the first 3 months, methotrexate was switched to oral administration maintaining the same dose. The primary efficacy outcome considered was the proportion of patients entering first remission after 3 and 6 months of therapy. Clinical remission was defined as the lack of need for steroid treatment and a Crohn's Disease Activity Index score of < or = 150 points at each scheduled visit. RESULTS: In the 54 patients (26 F, 28 M, mean age 34 years, range 18-60) randomly assigned to methotrexate (n=27) or azathioprine (n=27), no statistically significant difference was found between the two treatment regimens with respect to remission rate after 3 (methotrexate 44%, azathioprine 33%, p=0.28, (95% CI, 0.369-0.147), and 6 months (methotrexate 56%, azathioprine 63%, p=0.39, 95% CI, 0.187-0.335), respectively. Six patients withdrew from therapy due to adverse events: 3/27 (11%) in methotrexate and 3/27 (11%) in azathioprine. Drug-related adverse events (asthenia, nausea and vomiting) that did not require withdrawal from therapy were more frequent in the methotrexate group (azathioprine: 2/27 (7%); methotrexate: 12/27 (44%), p=0.00009). The frequency of these adverse events was comparable during the intravenous or oral administration of the drug. CONCLUSIONS: This study confirms that methotrexate is effective in inducing remission in patients with chronic active Crohn's disease, therapeutic efficacy being comparable, but not faster, than that of azathioprine.

Infliximab in treatment of Crohn's disease: the Milan experience.

BACKGROUND: Efficacy of infliximab in treatment of patients with moderate-to-severe refractory and fistulizing Crohn's disease has been shown in controlled clinical trials. Moreover, audit data from North America and North Europe have confirmed efficacy in clinical practice comparable to that in clinical trials. AIM: To report clinical experience using infliximab in treatment of Crohn's disease in Italy, comparing efficacy and safety with those reported in clinical trials and other published series. PATIENTS AND METHODS: The study population comprised 63 patients (31 males and 32 females, median age 33 years) treated with infliximab for refractory/inflammatory (31 patients) and/or fistulizing Crohn's disease (32 patients). All patients received an infusion of infliximab at a dose of 5 mg/kg at weeks 0, 2 and 6. After the first infusion, clinical and laboratory assessments were repeated at weeks 2, 6 and 10. For refractory inflammatory Crohn's disease, clinical remission was defined as a Crohn's Disease Activity Index of < or = 150 at each scheduled visit, clinical response as a reduction in the Crohn's Disease Activity Index score of > or = 70 points in comparison to baseline. For fistulizing Crohn's disease, a complete response was defined as closure of any draining fistulae at week 10. A fistula was defined as closed when it no longer drained despite gentle finger pressure. A partial response was defined as reduction in number, size or drainage of fistulae, at the same visit. RESULTS: According to an intention-to-treat evaluation on the 31 patients with refractory/inflammatory Crohn's disease, at week 2, 42.5% (14 patients) had a clinical response and 31.3% of patients (10 patients) were in clinical remission. At week 10 (4 weeks after the end of third infusion), 80.6% (25 patients) had a clinical response and 71% (22 patients) were in clinical remission and 14/19 (74%) had discontinued steroid treatment. Of the 32 patients with fistulizing Crohn's Disease, 15 (46.9%) had a complete response, 8 (25%) a partial response, and 9 (28.1%) no response at week 10 check-up. The incidence of side-effects was low (16%) and not influenced by concurrent immunomodulatory therapy. CONCLUSION: The present experience with infliximab in clinical practice confirms its efficacy, in particular in inflammatory/refractory Crohn's disease and its safety, at least, in short-term follow-up.

Infliximab-induced lupus in Crohn's disease: a case report.

An 18-year-old male patient was under treatment with infliximab at a dose of 5 mg/kg at Weeks 0, 2 and 6 for refractory Crohn's disease. In June 2002, the patient was admitted to the Outpatient Clinic of the Rheumatology Unit for arthralgia affecting the small joints, non-pruritic crops of purple skin lesions and malar rash in the face. Serum antinuclear antibodies were positive (1:640 speckled pattern), and anti-double-stranded DNA was positive (1:80); moreover, positivity of anti-extractable nuclear antigen was observed. Antihistone antibodies, lupus anticoagulant and anticardiolipin antibodies were negative. A diagnosis of infliximab-induced lupus was made and the drug treatment was withdrawn. However, 3 months after withdrawal of treatment, the patient still showed clinical and laboratory symptoms of systemic lupus erythematosus. After 6 months of treatment, systemic lupus erythematosus-related symptoms disappeared and anti-double-stranded DNA returned to normal. The patient is currently under treatment with prednisone 20 mg/day for systemic lupus erythematosus and with oral mesalazine 2.4 mg/day for Crohn's disease. Treatment with infliximab is known to produce an increase of autoantibodies (antinuclear antibodies, anti-double-stranded DNA), but not clinical disease. This is the first case, to our knowledge, of onset of prolonged infliximab-induced lupus.

[Efficacy of medical therapy in preventing the post-surgical recurrence in Crohn's disease]. / Efficacia della terapia medica nella prevenzione della recidiva post-chirurgica della malattia di Crohn.

Crohns Disease (CD) is a chronic intestinal inflammatory disease of unknown origins that cannot be definitely resolved with surgical intervention. Therefore, pharmacologic therapies are of great importance both in preventing relapses and by determining remissions. In this paper the authors analyse the different drugs available for the treatment of Crohns disease, and focus on their efficacy and tollerability.

Relationship among acid secretion, antral distension, and liquid gastric emptying in active and healed duodenal ulcer.

The aim of this study was to assess the relationship between fasting antral distension and basal and maximal acid output and to examine the link between the gastric emptying rate of liquids and the amount of acid secretion. Twenty consecutive male patients with H. pylori-positive noncomplicated duodenal ulcer disease received a measurement of basal and maximal gastric acid secretion and underwent ultrasonographic (US) evaluation of fasting antral distension and gastric emptying of liquids on two separate days. Ten of these patients were studied again three months after ulcer healing. The width of the fasting antral area was not correlated with basal acid output, but a significant relationship was found between maximal acid output and fasting antral distension (r = 0.55; P = 0.012). No significant correlations were found between gastric emptying and gastric acid output. The gastric emptying rate, expressed as half-time gastric emptying and remaining liquid component at 60 min, was not influenced by basal or maximal acid output. After ulcer healing, no correlations were found between acid secretion, fasting antral distension, and gastric emptying rate. Our results suggest that in duodenal ulcer patients, fasting antral distension is not influenced by basal gastric secretion and that, on the contrary, a correlation exists between fasting antral distension and maximal acid output, but only in active duodenal ulcer. No relationship exists in both active and healed duodenal ulcer between gastric emptying and gastric acid secretion.

Audit of reflux oesophagitis at 4 years.

BACKGROUND: Data on the natural history of reflux oesophagitis are few and conflicting: it is not clear whether in the long-term, patients still require therapy for controlling symptoms and preventing endoscopic relapse. AIMS: To assess, in reflux oesophagitis patients followed up for a median period of 4 years: a) clinical conditions throughout follow-up period (i.e., frequency of relapses, need and type of treatment, satisfaction with therapy; b) present state, including quality of life, mode of treatment, presence of residual symptoms or invalidity. PATIENTS: A series of 288 consecutive outpatients, diagnosed as having reflux oesophagitis during the period 1986-1990, and followed up for at least 48 months. METHODS: The study was carried out in two parts. The first, retrospective, assessing the outcome throughout follow-up during which it was suggested that patients assume a maintenance therapy with H2-receptor antagonists, proton pump inhibitors or other drugs for the first year, and to continue only if desired. Patients returned for follow-up every six months, and endoscopy was repeated after the first year or in the case of symptom recurrence. In the second part, after a median follow-up of 4 years, patients were submitted to a telephone interview by means of a structured questionnaire, assessing type and severity of current symptoms (if any), type of current therapy, degree of satisfaction with treatment, and overall evaluation of quality of life. RESULTS: Data are available from 132 patients (M/F = 85/47) of whom 119 (90%) were still on treatment and 31% still presented symptoms. During follow-up, 21% had more than 3 endoscopic relapses, 23% between 2 and 3, 28% one, and 28% zero, respectively and 79% were still adopting non-pharmacological measures (diet, posture, etc.). Only two (1.5%) had been submitted to surgery to control untractable symptoms/mucosal lesions. Finally, 64% and 11%, respectively, considered the present quality of life as good or excellent. CONCLUSIONS: Contrary to many reports, the prognosis of reflux oesophagitis is not favourable showing a marked trend to chronicity; the disease leads to almost continuous drug assumption for symptom control, and is associated with a high relapse risk after treatment withdrawal. Despite (or due to) these unfavourable features, patient compliance to both pharmacological and non-pharmacological therapy is excellent and, correspondingly, also the quality of life is acceptable or improved.

Ultrasonographic features of long-standing primary intestinal lymphangiectasia.

This article describes a case of primary intestinal lymphangiectasia associated with protein-losing enteropathy and lower right leg lympoedema in a 20-year-old woman. Echographic findings showed dilation of the intestinal loops, regular and diffuse thickening of the walls, plical hypertrophy and impressive mesenteric oedema. Although diagnosis of the disease is substantially histological, the ultrasonographic characteristics of the lesions are fairly indicative and of certain diagnosis usefulness in patients with protein-losing enteropathy.

Clinical and gastroscopic evaluation of amtolmetin guacyl versus diclofenac in patients with rheumatoid arthritis.

AIM: Amtolmetin guacyl (2-[2[1-methyl-5-(4-methylbenzoyl) pyrrol-2-yl] acetamido] acetic acid 2-methoxyphenyl ester) is a recently developed drug which, in preliminary studies, has shown effective anti-inflammatory properties with improved gastrointestinal safety. Our study was designed to investigate the efficacy and tolerability of amtolmetin guacyl 600 mg bid when compared to diclofenac 50 mg tid for 4 weeks. PATIENTS AND METHODS: A total of 64 patients aged 18-80 years, suffering from rheumatoid arthritis for more than 6 months and American Rheumatism Association functional class I, II or III were randomized in a double blind manner to amtolmetin guacyl or diclofenac for 4 weeks. Clinical and endoscopic evaluation were performed at baseline and at the end of the treatment. The mucosa was graded by means of a rating system emphasizing mucosal erosions. Only patients with endoscopy grade 0-1 entered the trial. RESULTS: The median post-treatment endoscopy injury scores were 0 (range 0-4) in the amtolmetin guacyl-treated patients and 2 (range 0-4) in the diclofenac-treated patients (p = 0.005). There were nine gastric ulcers: 1/32 (3%) in the amtolmetin guacyl group and 8/32 (25%) in the diclofenac group (p < 0.05; 95% confidence interval, -30-5%). 16/32 (50%) patients in amtolmetin guacyl group and 8/32 (25%) in diclofenac group had normal gastroduodenal findings (score = 0) (p < 0.05; 95% confidence interval, 5-50%). In patients with a history of peptic ulcer, a recurrence of gastric damage (score 3-4) was observed in 18% in the amtolmetin guacyl and in 53% in the diclofenac group (p < 0.05). The incidence of gastrointestinal symptoms did not differ in the two groups. Amtolmetin guacyl significantly reduced the number of swollen and painful joints, and the functional disability index; diclofenac significantly reduced the number of painful joints and the functional disability index score (p = ns). CONCLUSIONS: Amtolmetin guacyl effectively controlled the symptoms of rheumatoid arthritis, with very limited gastric toxicity. If these findings are confirmed on a wider scale, the drug might become a valid alternative to current therapies, especially for patients at risk, such as those with rheumatoid arthritis simultaneously requiring steroids and second-line drugs, or those with a history of peptic ulcer.

Prevention of gastroduodenal damage with omeprazole in patients receiving continuous NSAIDs treatment. A double blind placebo controlled study.

AIM: The aim of this study was to compare omeprazole (20 mg once daily) with placebo in the long-term prevention of gastroduodenal lesions induced by indomethacin, diclofenac and ketoprofen. PATIENTS AND METHODS: 114 patients with arthritic disorders and requiring indomethacin, diclofenac or ketoprofen were randomized in a double blind manner to receive omeprazole-20 mg once daily- or identical placebo for three weeks. The gastroduodenal mucosa damage was scored according to a 0-4 point endoscopic scale. RESULTS: Of the 114 patients, 103 (50 in the omeprazole group, 53 in the placebo group) were submitted to endoscopy, while 11 patients dropped out for non-medical reasons. At the final endoscopy, 26/57 (46%) of omeprazole group, and 20/57 (35%) of the placebo group had normal gastroduodenal mucosa (score = 0) (p ns; 95% IC -0.073 + 0.284). A gastric ulcer was observed in 7/57 (12%) patients, all in the placebo group (p < 0.01 vs omeprazole); 2 patients (1 in the omeprazole group and 1 in the placebo group) developed a duodenal ulcer. Dyspeptic symptoms developed in 10% of the patients treated with omeprazole and 29% of those receiving placebo (p ns). CONCLUSIONS: Omeprazole, 20 mg once daily, provides effective prophylactic therapy in patients at risk of developing NSAID-associated gastric and duodenal ulcer.

Effects of Helicobacter pylori eradication on gastric function indices in functional dyspepsia. A prospective controlled study.

BACKGROUND: To date, it is unclear whether Helicobacter pylori infection is associated with disturbances of gastric emptying or acid secretion in patients with functional dyspepsia (FD). Our aim was to investigate whether, in the long run, cure of H. pylori infection significantly influences gastric emptying of solids, acid secretion, and gastrin and pepsinogen I (PGI) release in patients with FD. METHODS: Thirty-eight consecutive H. pylori-positive patients with FD, whose complaints were scored for severity and frequency on the basis of a validated symptom questionnaire, were initially enrolled in the study. They were randomized to receive an eradicating regimen consisting of omeprazole plus clarithromycin and tinidazole for 1 week or full-dose ranitidine for 3 weeks. In 33 patients (18 H. pylori-cured and 15 with persistent infection) basal and pentagastrin-stimulated acid secretion, fasting and meal-induced gastrin concentrations, fasting serum PGI levels, and gastric emptying of solids were determined before and 6 months after therapy. RESULTS: In the 18 H. pylori-cured patients meal-induced gastrin and fasting PGI levels were significantly reduced after 6 months as compared with pretreatment values (peak serum gastrin, 76.0 +/- 23.4 versus 111.9+/-37.4 pg/ml; PGI, 57.1+/-23.4 versus 72.9+/-29.1 ng/ml), whereas they remained virtually unchanged in the 15 patients with persistent infection. In contrast, both basal and stimulated acid secretion and gastric emptying time of solids remained unmodified over time in both groups of patients. CONCLUSIONS: We confirm that also in patients with functional dyspepsia H. pylori eradication in the long run significantly reduces gastrin and PGI release as a result of improvement in the underlying antral gastritis, but this is not accompanied by modifications of gastric emptying of solids or acid secretion.